Diabetes mellitus is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose homeostasis. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body, however patients have a resistance to the effects of insulin in stimulating glucose and lipid metabolism in the insulin-sensitive tissues such as muscle, liver and adipose. Early stage of type 2 diabetes patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as the islet beta cells try to compensate for the reduced effectiveness of insulin by secreting increased amounts of insulin. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle; inadequate insulin-mediated repression of lipolysis in adipose tissue and glucose output from the liver.
Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Impaired glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic diseases. Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Patients who have insulin resistance often have Metabolic Syndrome with complications including vascular dysfunctions, atherosclerosis and coronary heart disease, (as defined in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670).
Pharmacologic treatments for diabetes have largely focused on three areas of pathophysiology: (1) hepatic glucose production (biguanides, such as phenformin and metformin), (2) insulin resistance (PPAR agonists, such as rosiglitazone, troglitazone, engliazone, balaglitazone, and pioglitazone), (3) insulin secretion (sulfonylureas, such as tolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics (GLP-1 derivatives and analogs, such as exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide and taspoglutide); and (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, such as sitagliptin, alogliptin, vildagliptin, linagliptin, denagliptin and saxagliptin).
The two best known biguanides, phenformin and metformin, demonstrated reasonable efficacy in controlling hyperglycemia with the adverse effect of lactic acidosis and nausea/diarrhea. PPAR gamma agonists, such as rosiglitazone and pioglitazone, are modestly effective in reducing plasma glucose and hemoglobin A1C. However, the currently marketed glitazones do not greatly improve lipid metabolism and may negatively effect on the lipid profile. The administration of insulin secretagogues, such as the sulfonylureas (e.g. tolbutamide, glipizide, and glimepiride) can result in hypoglycemia; their administration must therefore be carefully controlled.
Leukotriene B4 (LTB4) is a pro-inflammatory lipid mediator generated from arachidonic acid through the activities of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP) and leukotriene A4 hydrolase (LTA4H) (Samuelsson et al., Science 1987; 237:1171-1176, Haeggstrom, J Z, J. Biol Chem. 2004; 279:50639-50642).
LTB4 is a chemoattractant and regulates the proinflammatory cytokines by binding to a G-protein coupled receptor leukotriene B4 receptor 1 (BLT1) and leukotriene B4 receptor 2 (BLT2). LTB4 has been considered an endogenous mediator for the recruitment of inflammatory cells in acute and chronic disease states and has been associated with inflamed tissue in rheumatoid arthritis, psoriasis, inflammatory bowel disease and asthmas; and LTB4 receptor antagonists were developed for the treatment of variety of inflammatory diseases (Dalvie et al., Xenobiotica, 1999, Vol. 29, No. 11, 11-23-1140). The potent biological actions of LTB4 are mediated primarily through a high affiniity interaction with a G-protein coupled receptor termed BLT-1 (Yokomizo et al., Nature, 1997; 387:620-624). LTB4:BLT1 plays an important role in host defense during acute infection. Choronic activation of the LTB4:BLT1 pathway contributes to the development of inflammatory diseases such as atherosclerosis and arthritis. BLT1, a high affinity receptor specific for LTB4, is demonstrated to express predominantly in leucocytes. BLT2, a low affinity receptor for LTB4, is ubiquitiously expressed. In the 1990s, BLT1 and dual BLT1/BLT2 antagonists were pursued for treating inflammatory conditions including asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, cystic fibrosis, rheumatic arthritis and cancer. Recent publications suggest a potential BLT1 involvement in mediating tumor progression and the blockade of LTB4/BLT1 pathways could generate benefits in controlling tumor growth (Yokota et al., Blood, 2012; 120:3444-3454; Woo-Kwang Jeon et al., The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region, Oncotarget, Advance Publications 2015; and Wang, Luman et al., Am J Respir Crit Care Med 2012, 186: 989-998).
It was recently found that deficiency of BLT1 protects against the development of insulin resistance in diet-induced obesity by regulating adipose tissue macrophage accumulation and inflammation in insulin-sensitive tissues (Spite et al., J Immunol., 2011 Aug. 15, 187(4), 1942-1949). The study also found that 1) BLT1 deficiency improves glucose and insulin-tolerance in diet induced obese mouse model; 2) BLT1 is a key regulator of macrophage accumulation in adipose tissue and systemic insulin signaling; and 3) the BLT1 pathway points towards new avenues for the therapeutic management of obesity and type 2 diabetes (Spite et al., J Immunol., 2011, 15, 187(4), 1942-1949).
Compounds that are antagonists of leukotriene B4 receptor 1 (BLT1) may be useful to treat type 2 diabetes mellitus, obesity, hypertension, dyslipidemia, cancer, and metabolic syndrome, as well as cardiovascular diseases, such as myocardial infarction and stroke, by improving glucose and lipid metabolism, and by improving whole body energy homeostasis.
Leukotriene B4 (LTB4) receptor antagonists are disclosed in: WO 93/015066; WO 93/015067; WO 96/006604; WO 96/011920; WO 96/011925; WO 96/41645; WO 98/011119; WO 03/007947; WO 13/106238; U.S. Pat. Nos. 5,550,152; 5,552,435; 5,939,452; 6,051,601; 6,117,874; 6,133,286; US 2009/054466; US 2009/253684; US 2009/227603; EP00518819; Koch et al., J. Med. Chem., 1994, Vol. 37, No. 20, pp. 3197-3199; Showell et al., J. of Pharmacology and Experimental Therapeutics, Vol. 273, No. 1, pp. 176-184, 1995; Reiter et al., Bioorg. Med. Chem Lett. 8 (1998) 1781-1786; Chambers et al., Bioorg. Med. Chem. Lett. 8 (1998) 1787-1790; Reiter et al., Bioorg. Med. Chem. Lett. 7 (1997) 2307-2312; Showell et al., J. of Pharmacology and Experimental Therapeutics, Vol. 285, No. 3, pp. 946-954, 1998; Dalvie et al., Xenobiotica, 1999, Vol. 29, No. 11, 11-23-1140; Jones et al., Heterocycles, Vol. 53, No. 8, 2000, pp. 1713-1724; and Khojasteh-Bakht et al., Xenobiotica, December 2003, Vol. 33, No. 12, 1201-1210.
Hydroxy tetralins are disclosed in U.S. Pat. Nos. 5,215,989; 5,032,598; and EP 0 431 945.